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Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11)

Open AccessPublished:August 08, 2020DOI:https://doi.org/10.1016/j.jtho.2020.07.014

      Abstract

      Introduction

      Sintilimab, an anti–programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to compare the efficacy and safety of sintilimab with placebo, both in combination with such chemotherapy (ClinicalTrials.gov: NCT03607539).

      Methods

      A total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or anaplastic lymphoma kinase genomic aberration were randomized (2:1 ratio) to receive either sintilimab 200 mg or placebo plus pemetrexed and platinum once every 3 weeks for four cycles, followed by sintilimab or placebo plus pemetrexed therapy. Crossover or treatment beyond disease progression was allowed. The primary end point was progression-free survival (PFS) as judged by an independent radiographic review committee.

      Results

      As of November 15, 2019, the median follow-up was 8.9 months. The median PFS was significantly longer in the sintilimab-combination group than that in the placebo-combination group (8.9 versus 5.0 mo; hazard ratio, 0.482, 95% confidence interval [CI]: 0.362–0.643; p < 0.00001). The confirmed objective response rate was 51.9% (95% CI: 45.7%–58.0%) in the sintilimab-combination group and 29.8% (95% CI: 22.1%–38.4%) in placebo-combination group. The incidence of grade 3 or higher adverse events was 61.7% in sintilimab-combination group and 58.8% in placebo-combination group.

      Conclusions

      In Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone with manageable safety profiles.

      Keywords

      Introduction

      Anti–programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) antibodies are effective therapies for previously untreated patients with metastatic nonsquamous NSCLC who do not harbor driver gene mutations.
      • Reck M.
      • Rodriguez-Abreu D.
      • Robinson A.G.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      • Gandhi L.
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      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      • West H.
      • McCleod M.
      • Hussein M.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.
      Despite anti–PD-1 antibody (pembrolizumab) monotherapy prolonging overall survival (OS) compared to the standard chemotherapy among patients with a PD-L1 tumor proportion score (TPS) of 1% or greater, such benefit is more remarkable in patients with a PD-L1 TPS of 50% or greater,
      • Reck M.
      • Rodriguez-Abreu D.
      • Robinson A.G.
      • et al.
      Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
      ,
      • Mok T.S.K.
      • Wu Y.L.
      • Kudaba I.
      • et al.
      Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial.
      who only represents a minority of those with nonsquamous NSCLC. Of note, first-line combination regimens that include a PD-1 or PD-L1 inhibitor and chemotherapy result in longer OS than chemotherapy alone in patients with any level of PD-L1 expression.
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      • West H.
      • McCleod M.
      • Hussein M.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.
      Differences between Asian and non-Asian patients in safety profiles have been reported for immunotherapy.
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      • Shi H.
      Management of adverse events in cancer patients treated with PD-1/PD-L1 blockade: focus on Asian populations.
      In addition, the difference in genetic driver profiles between these two populations may also affect the efficacy of immunotherapy.
      • Kim J.H.
      • Kim H.S.
      • Kim B.J.
      Prognostic value of KRAS mutation in advanced non-small-cell lung cancer treated with immune checkpoint inhibitors: a meta-analysis and review.
      • Ng T.L.
      • Liu Y.
      • Dimou A.
      • et al.
      Predictive value of oncogenic driver subtype, programmed death-1 ligand (PD-L1) score, and smoking status on the efficacy of PD-1/PD-L1 inhibitors in patients with oncogene-driven non-small cell lung cancer.
      • Ferrer I.
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      • Herbertz S.
      • John W.
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      KRAS-mutant non-small cell lung cancer: from biology to therapy.
      • Zhou W.
      • Christiani D.C.
      East meets West: ethnic differences in epidemiology and clinical behaviors of lung cancer between East Asians and Caucasians.
      However, data on immunotherapy for patients from Asia, including People’s Republic of China, are limited: proportion of patients from Asia only account for 3% to 14% in KEYNOTE-189, IMpower150, and IMpower130 studies.
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      • West H.
      • McCleod M.
      • Hussein M.
      • et al.
      Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial.
      • Socinski M.A.
      • Jotte R.M.
      • Cappuzzo F.
      • et al.
      Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC.
      Therefore, it is crucial to evaluate the efficacy and safety of immunocombination treatments in the Chinese population.
      Sintilimab is a selective anti–PD-1 antibody that inhibits interactions between PD-1 and its ligand, PD-L1. Compared with pembrolizumab or nivolumab, sintilimab has a different binding site and potentially greater affinity against PD-1 as per the preclinical data.
      • Wang J.
      • Fei K.
      • Jing H.
      • et al.
      Durable blockade of PD-1 signaling links preclinical efficacy of sintilimab to its clinical benefit.
      In a phase 1b study, sintilimab plus pemetrexed and platinum has been found to have tolerable safety profile and promising efficacy in previously untreated patients with nonsquamous NSCLC, with an objective response rate (ORR) of 68.4% and a median progression-free survival (PFS) of 11.4 months.
      • Xu N.
      • Ying K.
      • Wang Z.
      • et al.
      Phase Ⅰb study of sintilimab in combination with chemotherapy for 1L advanced or metastatic non-small cell lung cancer (NSCLC).
      In this randomized, double-blind, phase 3 study (ORIENT-11), we compared the combination of pemetrexed and platinum plus either sintilimab or a placebo in Chinese patients with locally advanced or metastatic nonsquamous NSCLC.

      Materials and Methods

      Study Design

      This randomized, double-blind, phase 3 study was conducted in 47 hospitals in the People’s Republic of China. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization guidelines on good clinical practice. Ethical approval was sought and granted at each center. All patients provided written informed consent before any study-specific procedures.
      The patients were randomly assigned (2:1) to receive either sintilimab or placebo, in combination with pemetrexed and platinum, stratified by sex (male or female), choice of platinum (cisplatin or carboplatin), and PD-L1 TPS (≥1% or <1%). An interactive web response system was used to assign patients as per predefined randomization. Investigators, participants, and individuals who did assessments and analyses were blinded. Sintilimab and placebo were packaged identically to maintain the blinding.

      Patients

      Eligible patients were aged 18 to 75 years old with histologically or cytologically confirmed stage IIIB to IV nonsquamous NSCLC (according to eighth edition of TNM classification by the International Association for the Study of Lung Cancer Staging project
      • Rami-Porta R.
      • Bolejack V.
      • Giroux D.J.
      • et al.
      The IASLC lung cancer staging project: the new database to inform the eighth edition of the TNM classification of lung cancer.
      ) who were ineligible for radical surgery or radiotherapy, had no sensitive EGFR mutations or anaplastic lymphoma kinase rearrangements, had at least one measurable lesion based on the Response Evaluation Criteria in Solid Tumors version 1.1,
      • Eisenhauer E.A.
      • Therasse P.
      • Bogaerts J.
      • et al.
      New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).
      had no previous systemic treatment for advanced and metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1, with adequate hepatic, renal, hematological, and blood coagulative function and a life expectancy of at least 3 months. Patients were excluded if they had symptomatic central nervous system metastases, had previous immune checkpoint inhibitor treatment, required long-term systemic glucocorticoid treatment, and had active hepatitis B virus or hepatitis C virus infection. Full eligibility criteria are listed in the trial protocol.

      Treatment and Assessments

      Sintilimab 200 mg or placebo was intravenously (IV) administered on day 1 of each cycle, once every 3 weeks (Q3W), in combination with pemetrexed (500 mg/m2 IV on day 1 Q3W) and either cisplatin (75 mg/m2 IV on day 1 Q3W) or carboplatin (area under the concentration–time curve, 5 mg/mL/min IV on day 1 Q3W) for four cycles as induction therapy, followed by sintilimab 200 mg or placebo in combination with pemetrexed (500 mg/m2) as maintenance therapy Q3W for up to 24 months. The treatment was continued until disease progression, intolerable toxicity, initiation of new treatment, or withdrawal of consent.
      Patients with radiographic disease progression but who were clinically stable could continue the treatment at the investigator’s discretion until disease progression was confirmed at least 4 weeks after the imaging assessment that first revealed disease progression. For patients with verified disease progression by an independent radiographic review committee (IRRC), study group assignment could be unmasked. Patients in the sintilimab-combination group who were deemed to have clinical benefit from the therapy could continue treatment beyond disease progression. Patients in the placebo-combination group were eligible to cross over to receive sintilimab monotherapy if they met all protocol-specified criteria.
      Tumor imaging was conducted at baseline, week 6, week 12, and then every 9 weeks through week 48 and every 12 weeks thereafter, by contrast-enhanced computed tomography and magnetic resonance imaging. The response was assessed on the basis of the Response Evaluation Criteria in Solid Tumors version 1.1. Complete and partial responses were confirmed by repeat tumor imaging assessment no less than 4 weeks from the date the response was first documented. Adverse events (AEs) were monitored during the study treatment and till 90 days after the treatment ended. The AEs were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03. For the follow-up, the patients were contacted every 3 months to assess survival.
      PD-L1 expression was assessed in archived tumor tissue or recent biopsy specimen. The PD-L1 immunohistochemistry 22C3 pharmDx assay (Agilent Technologies) was used to assess PD-L1 expression during screening at a central laboratory (Covance, Shanghai, People’s Republic of China). Tumor PD-L1 expression was measured by TPS, which is the percentage of viable tumor cells revealing partial or complete membrane staining at any intensity.

      End points

      The primary end point was PFS (defined as the time from randomization to disease progression assessed by blinded IRRC or death from any cause, whichever occurred first). The secondary end points included OS (defined as the time from randomization to death from any cause), ORR (defined as the proportion of patients with a confirmed complete or partial response), disease control rate (DCR, defined as the proportion of patients with a confirmed complete or partial response or stable disease), time to response (defined as the time from randomization to the first documented objective tumor response), duration of response (DoR, defined as the time from first documented complete or partial response to disease progression or death), and safety.

      Statistical Analysis

      The study planned to enroll approximately 378 patients (in 2:1 ratio) to achieve 263 PFS events, which would have a power of 90% to detect a hazard ratio (HR) of 0.65 at two-sided alpha level of 0.05 for comparison between the sintilimab-combination group and the placebo-combination group, allowing for a dropout rate of 0.5% per month.
      Efficacy analyses included all patients randomly assigned to a group according to the intention-to-treat principle, whether they had received treatment or not. Safety analyses included all patients who received at least one dose of study treatment. All statistical analyses were conducted using the SAS version 9.4 (SAS Institute Inc.).
      The Kaplan-Meier method was used to analyze PFS, OS, and DoR. Data for patients who were alive and did not have disease progression or who initiated new anticancer therapy were censored for the analysis of PFS at the time of the last imaging assessment before starting new anticancer therapy. Data for patients who were alive or lost to follow-up were censored for OS at the time they were last known to be alive; data for patients who crossed over were not censored at the time of crossover. The stratified log-rank test was used to evaluate the treatment difference. The HRs and associated 95% confidence intervals (CIs) were calculated based on a stratified Cox proportional-hazards model. The Clopper-Pearson method was used to calculate the 95% CI of ORR and DCR for each treatment group. Between-group differences in ORR and DCR were assessed using the stratified Miettinen and Nurminen method. Descriptive statistics were provided for safety data. The randomization stratification factors were applied to all stratified efficacy analyses.
      Subgroup analyses of PFS were prespecified in the statistical analysis plan that was finalized before database lock and unblinding of the study. In each subgroup, the HR and its 95% CI were estimated from the stratified Cox model. The survival curves and median survival of the subgroups were based on the Kaplan-Meier method.
      An interim analysis was planned to be performed when 70% of PFS events (i.e., 184 events) were achieved. As of the data cutoff on November 15, 2019, there were 198 events of disease progression or death, and the multiplicity adjusted, one-sided alpha spent at this interim analysis (as determined on the basis of the Lan-DeMets O’Brien-Fleming spending function) was 0.00979 for PFS. The results of the interim analysis were reviewed by the Independent Data Monitoring Committee, which reported that statistically significant difference in PFS met the prespecified criteria. This trial continues to accumulate long-term data. All data reported here were based on the interim analysis.

      Results

      Between August 23, 2018 and July 30, 2019, a total of 862 patients were screened, of whom 397 were enrolled and randomly assigned to the sintilimab-combination (n = 266) and placebo-combination groups (n = 131) (Supplementary Fig. 1). The demographic and disease characteristics at baseline were well balanced between the two groups (Table 1).
      Table 1Baseline Characteristics of Demographic and Disease
      CharacteristicSintilimab-Combination (N = 266)Placebo-Combination (N = 131)
      Age, y
       Median (range)61 (30, 75)61 (35, 75)
       >60, n (%)140 (52.6)71 (54.2)
      Sex, n (%)
       Male204 (76.7)99 (75.6)
       Female62 (23.3)32 (24.4)
      ECOG score, n (%)
       076 (28.6)34 (26.0)
       1190 (71.4)97 (74.0)
      Smoking status, n (%)
       Never95 (35.7)44 (33.6)
       Current49 (18.4)23 (17.6)
       Former122 (45.9)64 (48.9)
      Disease stage, n (%)
       IIIB14(5.3)6 (4.6)
       IIIC7 (2.6)9 (6.9)
       IV245 (92.1)116 (88.5)
      Histologic features, n (%)
       Adenocarcinoma253 (95.1)123 (93.9)
       Large-cell carcinoma2 (0.8)3 (2.3)
       NSCLC not otherwise specified4 (1.5)3 (2.3)
       Other7 (2.6)2 (1.5)
      PD-L1 TPS, %, n (%)
       <185 (32.0)44 (33.6)
       ≥1181 (68.0)87 (66.4)
      ≥1 to <5074 (27.8)26 (19.8)
      ≥50107 (40.2)61(46.6)
      Platinum choice, n (%)
       Cisplatin71 (26.7)33 (25.2)
       Carboplatin195 (73.3)98 (74.8)
      Brain metastases, n (%)36 (13.5)22 (16.8)
      ECOG, Eastern Cooperative Oncology Group; PD-L1, programmed death ligand 1; TPS, tumor proportion score.
      At the data cutoff on November 15, 2019, the median follow-up was 8.9 months (range, 0.6–14.8). In all, 227 patients (85.3%) in the sintilimab-combination group and 105 patients (80.2%) in the placebo-combination group completed four cycles of induction treatment and received maintenance therapy. The main reason, in both groups, for treatment discontinuation in the induction phase was disease progression, - 21 patients (7.9%) in the sintilimab-combination group and 13 patients (9.9%) in the placebo-combination group. The median number of maintenance treatment cycles was seven (range, 1–17) in the sintilimab-combination group and four (range, 1–17) in the placebo-combination group. The main reason, in both groups, for maintenance therapy discontinuation was also disease progression, -56 patients (21.1%) in the sintilimab-combination group and 48 patients (36.6%) in the placebo-combination group. There were 151 patients (56.8%) in the sintilimab-combination group and 46 patients (35.1%) in the placebo-combination group who were still receiving the assigned treatment (Supplementary Fig. 1). The median duration of treatment was 7.1 months for the sintilimab-combination group and 5.5 months for the placebo-combination group. In the placebo-combination group, 35 patients (26.7%) were crossed over to receive sintilimab monotherapy during the study after confirmed disease progression, and six patients (4.6%) had received immunotherapy outside the study, which resulted in an effective crossover rate of 31.3%. In total, 129 patients (32.5%) continued the study treatment beyond the first disease progression, with 83 patients (31.2%) in the sintilimab-combination group and 46 patients (35.1%) in the placebo-combination group.
      At the time of the data cutoff, 112 patients (42.1%) in the sintilimab-combination group and 86 patients (65.6%) in the placebo-combination group had IRRC–assessed PFS events. The median PFS was 8.9 (95% CI: 7.1–11.3) months in the sintilimab-combination group and 5.0 (95% CI: 4.8–6.2) months in the placebo-combination group (HR, 0.482; 95% CI: 0.362–0.643; p < 0.00001) (Fig. 1A). The PFS rates at 6 months were 68.3% (95% CI: 62.0–73.8) in the sintilimab-combination group and 42.0% (95% CI: 32.8–50.9) in the placebo-combination group. The HR was 0.578 (95% CI: 0.283–1.180) and 0.468 (95% CI: 0.342–0.641) for patients with and without brain metastases, respectively (Fig. 1B). Benefit associated with the addition of sintilimab was also observed in patients who never smoked, with an HR of 0.558 (95% CI: 0.337–0.924) (Fig. 1B).
      Figure thumbnail gr1
      Figure 1(A) Kaplan-Meier plots for PFS in all randomized patients and (B) forest plot of HRs for PFS according to patient characteristics at baseline. Chemo, chemotherapy (pemetrexed and platinum); CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; PD-L1, programmed death ligand 1; PFS, progression-free survival; PL, placebo; PS, performance status; Sint, sintilimab; Yr, year.
      In patients with PD-L1 TPS of less than 1%, the median PFS was 7.3 months (95% CI: 6.2–NR) in the sintilimab-combination group and 5.1 months (95% CI: 4.6–7.8) in the placebo-combination group (HR, 0.664; 95% CI: 0.406–1.086, p = 0.10295) (Fig. 2A). In patients with PD-L1 TPS of 1% to 49%, the median PFS was 7.1 months (95% CI: 6.1–9.2) in the sintilimab-combination group and 4.8 months (95% CI: 2.5–8.0) in the placebo-combination group (HR, 0.503; 95% CI: 0.276–0.918, p = 0.02506) (Fig. 2B). In patients with PD-L1 TPS of greater than or equal to 50%, the median PFS was not reached (95% CI: 9.2–NR) in the sintilimab-combination group and was 5.0 months (95% CI: 4.3–6.8) in the placebo-combination group (HR, 0.310; 95% CI: 0.197–0.489, p < 0.00001) (Fig. 2C).
      Figure thumbnail gr2
      Figure 2Kaplan-Meier plots for PFS according to PD-L1 TPS. (A) Tumor proportion score of <1%, (B) tumor proportion score of 1%–49%, and (C) tumor proportion score of ≥50%. Chemo, chemotherapy (pemetrexed and platinum); CI, confidence interval; HR, hazard ratio; NA, not applicable; PD-L1, programmed death ligand 1; PFS, progression-free survival; PL, placebo; Sint, sintilimab; TPS, tumor proportion score.
      A total of 51 patients (19.2%) in the sintilimab-combination group and 39 patients (29.8%) in the placebo-combination group had death events (Fig. 3). The median OS was not reached but revealed an improving trend in the sintilimab-combination group (HR, 0.609, 95% CI: 0.400–0.926).
      Figure thumbnail gr3
      Figure 3Kaplan-Meier plots for OS in all randomized patients. Chemo, chemotherapy (pemetrexed and platinum); CI, confidence interval; HR, hazard ratio; NR, not reached; OS, overall survival; PL, placebo; Sint, sintilimab.
      The confirmed ORR assessed by IRRC was significantly higher in the sintilimab-combination group (51.9%, 95% CI: 45.7–58.0) than that in the placebo-combination group (29.8%, 95% CI: 22.1–38.4) (p = 0.00003) (Supplementary Table 1). DCR assessed by IRRC was 86.8% (95% CI: 82.2–90.7) in the sintilimab-combination group and 75.6% (95% CI: 67.3–82.7) in the placebo-combination group (Supplementary Table 1). The median DoR was not reached (95% CI: 8.0–NR) in the sintilimab-combination group and was 5.5 months (95% CI: 4.1–10.9) in the placebo-combination group. The median time to response was 1.5 months (range, 1.2–7.0) in the sintilimab-combination group and 2.6 (range, 1.2–5.1) in the placebo-combination group (Supplementary Table 1). Improvement in confirmed ORR was observed in all subgroups defined according to PD-L1 TPS: among patients with PD-L1 TPS of less than 1%, the ORR was 38.8% (95% CI: 28.4–50.0) in the sintilimab-combination group versus 20.5% (95% CI: 9.8–35.3) in the placebo-combination group; among patients with PD-L1 TPS of 1% to 49%, it was 43.2% (95% CI: 31.8–55.3) versus 23.1% (95% CI: 9.0–43.7); and among patients with PD-L1 TPS of greater than or equal to 50%, it was 68.2% (95% CI: 58.5–76.9) versus 39.3% (95% CI: 27.1–52.7).
      AEs of any grade, regardless of attribution to study treatment as assessed by investigators, occurred in 265 patients (99.6%) in the sintilimab-combination group and in 131 patients (100.0%) in the placebo-combination group. AEs of grade 3 or higher occurred in 164 patients (61.7%) in the sintilimab-combination group and in 77 patients (58.8%) in the placebo-combination group. AEs that led to discontinuation of any investigational drugs occurred in 16 patients (6.0%) in the sintilimab-combination group and in 11 patients (8.4%) in the placebo-combination group. AEs that led to death occurred in six patients (2.3%) in the sintilimab-combination group and in nine patients (6.9%) in the placebo-combination group (Table 2).
      Table 2AEs of Any Cause
      EventSintilimab-Combination (N = 266)Placebo-Combination (N = 131)
      All Grade≥ Grade 3All Grade≥ Grade 3
      Any event265 (99.6)164 (61.7)131 (100.0)77 (58.8)
       AE led to any treatment discontinuation16 (6.0)12 (4.5)11 (8.4)9 (6.9)
      AE led to sintilimab or placebo discontinuation14 (5.3)10 (3.8)9 (6.9)9 (6.9)
      AE led to pemetrexed discontinuation10 (3.8)9 (3.4)10 (7.6)8 (6.1)
      AE led to platinum discontinuation4 (1.5)4 (1.5)3 (2.3)2 (1.5)
       AE led to death
      AE led to death in sintilimab-combination group including: respiratory failure, asphyxia, cardiac failure, cardiovascular disorder, cerebral hemorrhage, and febrile neutropenia; and in placebo-combination group including: dyspnea, interstitial lung disease, cardiac failure, cerebral artery embolism, cerebral infarction, cerebrovascular accident, decreased platelet count, infectious pericarditis constrictive, and pneumonia.
      6 (2.3)6 (2.3)9 (6.9)9 (6.9)
      Event occurring in ≥15% patients in any group
       Anemia197 (74.1)40 (15.0)103 (78.6)25 (19.1)
       Decreased neutrophil count189 (71.1)97 (36.5)82 (62.6)40 (30.5)
       Decreased white blood count180 (67.7)39 (14.7)84 (64.1)20 (15.3)
       Decreased platelet113 (42.5)32 (12.0)41 (31.3)16 (12.2)
       Increased aspartate aminotransferase109 (41.0)1 (0.4)51 (38.9)1 (0.8)
       Increased alanine aminotransferase108 (40.6)051 (38.9)4 (3.1)
       Nausea108 (40.6)4 (1.5)55 (42.0)0
       Decreased appetite101 (38.0)041 (31.3)1 (0.8)
       Asthenia87 (32.7)2 (0.8)42 (32.1)2 (1.5)
       Vomiting76 (28.6)2 (0.8)41 (31.3)0
       Constipation71 (26.7)042 (32.1)0
       Pyrexia55 (20.7)019 (14.5)1 (0.8)
       Hypoalbuminaemia52 (19.5)022 (16.8)0
       Decreased weight22 (8.3)2 (0.8)23 (17.6)2 (1.5)
      AE, adverse event.
      AEs that occurred during crossover phase were excluded.
      a AE led to death in sintilimab-combination group including: respiratory failure, asphyxia, cardiac failure, cardiovascular disorder, cerebral hemorrhage, and febrile neutropenia; and in placebo-combination group including: dyspnea, interstitial lung disease, cardiac failure, cerebral artery embolism, cerebral infarction, cerebrovascular accident, decreased platelet count, infectious pericarditis constrictive, and pneumonia.
      The most common AEs in both groups were anemia (74.1% versus 78.6%), decreased neutrophil count (71.1% versus 62.6%), and decreased white blood count (67.7% versus 64.1%). The most common grade 3 or higher AEs were decreased neutrophil count (36.5% versus 30.5%), anemia (15.0% versus 19.1%), and decreased white blood count (14.7% versus 15.3%) (Table 2).
      Immune-related AEs (irAEs), assessed by investigators who were blinded to the study group assignment, occurred in 115 patients (43.2%) in the sintilimab-combination group and in 48 patients (36.6%) in the placebo-combination group, with events of grade 3 or higher occurring in 15 patients (5.6%) and eight patients (6.1%), respectively (Table 3).
      Table 3Immune-Related AEs
      EventSintilimab-Combination (N = 266)Placebo-Combination (N = 131)
      All Grade≥ Grade 3All Grade≥ Grade 3
      Any event115 (43.2)15 (5.6)48 (36.6)8 (6.1)
      Hypothyroidism19 (7.1)07 (5.3)0
       Rash17 (6.4)1 (0.4)6 (4.6)3 (2.3)
       Increased aspartate aminotransferase16 (6.0)07 (5.3)0
       Increased alanine aminotransferase15 (5.6)07 (5.3)0
       Increased thyroid stimulating hormone13 (4.9)03 (2.3)0
       Hyperthyroidsm12 (4.5)02 (1.5)0
       Diarrhea12 (4.5)05 (3.8)0
       Immune-mediated pneumonitis9 (3.4)2 (0.8)2 (1.5)1 (0.8)
       Decreased thyroid stimulating hormone9 (3.4)03 (2.3)0
       Increased amylase8 (3.0)3 (1.1)10 (7.6)0
       Pruritus6 (2.3)04 (3.1)0
       Increased free thyroxine3 (1.1)04 (3.1)0
      AE, adverse event.
      Listed any event in more than 2% patients in any group. Immune-related AEs that occurred during crossover phase were excluded.

      Discussion

      The results of this phase 3 trial involving Chinese patients with previously untreated locally advanced or metastatic nonsquamous NSCLC revealed that the addition of sintilimab to standard chemotherapy with pemetrexed and platinum, as compared with chemotherapy alone, significantly prolonged median PFS by 3.9 months (8.9 mo versus 5.0 mo, HR, 0.482, p < 0.00001). A higher response rate was also observed in the sintilimab-combination group.
      The magnitude of PFS benefit observed in this study (HR, 0.482) was comparable with that observed in the KEYNOTE-189 study (HR, 0.52).
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      In addition, the trend of PFS benefit associated with the sintilimab combination was observed in all subgroups of PD-L1 TPS, with stepwise treatment effect according to PD-L1 expression (HR 0.664 in PD-L1 TPS <1%; HR 0.503 in PD-L1 TPS 1%–49%; HR 0.310 in PD-L1 TPS ≥50%). These findings were also consistent with the results of the KEYNOTE-189 study (HR 0.75 in PD-L1 TPS <1%; HR 0.55 in PD-L1 TPS 1%–49%; HR 0.36 in PD-L1 TPS ≥50%).
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      Of note, the PFS benefit in patients with a score of less than 1% was not statistically significant, because the ORIENT-11 study was not powered to detect a significant difference within subgroups.
      Brain metastasis is a poor prognostic factor for NSCLC.
      • Kawabe T.
      • Phi J.H.
      • Yamamoto M.
      • Kim D.G.
      • Barfod B.E.
      • Urakawa Y.
      Treatment of brain metastasis from lung cancer.
      However, the KEYNOTE-189 study revealed that although patients with brain metastases had worse outcomes compared to patients without brain metastases, the treatment effect associated with the addition of pembrolizumab to chemotherapy sustained, with an HR of 0.42.
      • Gadgeel S.
      • Rodríguez-Abreu D.
      • Speranza G.
      • et al.
      Updated analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer.
      In our study, prolonged PFS of patients with brain metastases was also observed more in the sintilimab-combination group than in the placebo-combination group (HR 0.578). However, the HR upper boundary crossed 1 (0.283–1.180), which might be due to relatively small sample size. Therefore, the benefit of sintilimab-combination in patients with brain metastases needs further confirmation in a larger cohort.
      As the time of data cutoff, median OS was not reached in either group. In addition, OS was not a predefined primary end point in this study. Nevertheless, the preliminary result was encouraging: sintilimab combined with pemetrexed and platinum reduced the risk of death by 39.1%, compared with pemetrexed and platinum alone. Long-term follow-up is definitely needed to evaluate the OS benefit associated with the combination therapy.
      Overall, sintilimab-combination was well tolerated, with low frequencies of dose discontinuation (6%) and death (2.3%) because of AEs. The AE profile observed in this study was consistent with the previously reported safety profile of sintilimab,
      • Shi Y.
      • Su H.
      • Song Y.
      • et al.
      Safety and activity of sintilimab in patients with relapsed or refractory classical Hodgkin lymphoma (ORIENT-1): a multicentre, single-arm, phase 2 trial.
      pemetrexed, and platinum,
      • Scagliotti G.V.
      • Parikh P.
      • von Pawel J.
      • et al.
      Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.
      with no new safety signals identified. Anemia, decreased neutrophil count, and decreased white blood count were the most frequently reported AEs in both groups. These were expected AEs associated with pemetrexed and platinum
      Food and Drug Administration
      Cisplatin injection prescribing information.
      Food and Drug Administration
      PARAPLATIN (carboplatin) injection.
      Food and Drug Administration
      ALIMTA (pemetrexed for injection) prescribing information.
      and were manageable, without leading to death or treatment discontinuation in our study.
      To date, the differences of irAE profiles between Asian and non-Asian patients remained to be elucidated. It had been noted that the incidence of immune-related or immune-mediated pneumonitis in Japanese patients (8%–14%)
      • Yamaguchi T.
      • Shimizu J.
      • Hasegawa T.
      • et al.
      Pre-existing pulmonary fibrosis is a risk factor for anti-PD-1-related pneumonitis in patients with non-small cell lung cancer: a retrospective analysis.
      ,
      • Nishio M.
      • Hida T.
      • Atagi S.
      • et al.
      Multicentre phase II study of nivolumab in Japanese patients with advanced or recurrent non-squamous non-small cell lung cancer.
      was higher compared with the non-Asian population.
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
      On the contrary, Asian patients reported less immune-related diarrhea (2%)
      • Wu Y.L.
      • Lu S.
      • Cheng Y.
      • et al.
      Nivolumab versus docetaxel in a predominantly Chinese patient population with previously treated advanced NSCLC: CheckMate 078 randomized phase III clinical trial.
      than the global population (6%).
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
      In this study, the incidence of immune-mediated pneumonitis was 3.4% in the sintilimab-combination group, which was consistent with that of the KEYNOTE-189 study (4.4%).
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      The incidence of immune-related diarrhea in our study was 4.5%. In the KEYNOTE-189 study, such incidence was not reported, because diarrhea was not included in the prespecified list of irAE terms used in that study.
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      On the basis of the overall incidence of diarrhea that occurred in the KEYNOTE-189 study (30.9%)
      • Gandhi L.
      • Rodriguez-Abreu D.
      • Gadgeel S.
      • et al.
      Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.
      and in our study (13.2%), it seems that Asian patients might be less susceptible to gastrointestinal toxicities of immunotherapy. However, direct comparisons of results between different studies might be misleading, and the differences of irAE profiles between Asian and non-Asian patients warrant further investigation.
      A limitation of this study was the short duration of the follow-up, because the interim analysis was event-driven and not time-driven. The short follow-up prevented the reporting of 12- and 24-month PFS rates. In addition, at the time of data cutoff, the number of OS events was also not mature enough to support full assessment. However, given the promising results from the preliminary analysis, we expect that the benefit observed in the sintilimab-combination group will be maintained with longer follow-up. Another limitation of the study was lack of comprehensive analysis of predictive biomarkers, such as tumor mutation burden and serine/threonine kinase 11 mutations, but this work is underway and will be reported in the near future.
      In conclusion, the addition of sintilimab to standard chemotherapy with pemetrexed and a platinum-based drug in Chinese patients with previously untreated locally advanced or metastatic nonsquamous NSCLC resulted in important longer PFS with manageable safety profiles. Thus, the combination regimen could provide a new treatment option for this patient population.

      Acknowledgments

      The authors thank the patients and their families who made this trial possible; the clinical study teams who participated in the study; Yuan Fang (Innovent Biologics, Inc.) for writing assistance; Xia Yin (Innovent Biologics, Inc.) for editorial assistance; and Leena Gandhi for scientific consulting support. The study was supported by Innovent Biologics, Inc., People’s Republic of China , and Eli Lilly and Company, United States . Innovent Biologics, Inc., was involved in the design and conduct of the study and in the collection, management, analysis, and interpretation of the data.

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      Linked Article

      • Comparing Immunotherapies in Combination With Chemotherapy for Previously Untreated Advanced Nonsquamous NSCLC
        Journal of Thoracic OncologyVol. 15Issue 12
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          We read with great interest the work of Yang et al.1 (ORIENT-11) comparing sintilimab, an anti–programmed cell death protein 1 (PD-1) antibody, in combination with chemotherapy, and appreciate their contributions to the treatment of advanced nonsquamous NSCLC in Asia. In fact, the U.S. Food and Drug Administration approved this indication on the basis of a very similar phase 3 study (KEYNOTE-189) around 2 years ago.2 We performed an adjusted indirect comparison between the results of ORIENT-11 and updated KEYNOTE-1893 using the methods described previously.
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      • Another Brick in the Wall: Sintilimab Plus Chemotherapy in Advanced Lung Cancer
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          For patients not suitable for single-agent immunotherapy, programmed death-(ligand) 1 (PD-[L]1) immune checkpoint blockade in combination with platinum-based chemotherapy has become a standard treatment for newly diagnosed advanced and metastatic NSCLC without a targetable genetic alteration. Specifically for nonsquamous NSCLC, we currently have the following four randomized studies revealing sufficient safety and overall survival (OS) benefit of PD-(L)1 blockade plus chemotherapy: KEYNOTE-189, IMpower150, IMpower130, and CheckMate 9LA.
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